A Phase II, Open-label Study of Bortezomib Following Nonmyeloablative Allogeneic Stem Cell Transplant in Patients With High-risk Multiple Myeloma
Multiple myeloma is a morbid disease associated with a poor outcome, particularly those with
high-risk cytogenetics. While standard therapies have modestly improved survival in these
high-risk patients, myeloma remains incurable. To date, the only potential curative
treatment remains allogeneic hematopoietic stem cell transplantation. However, the high
incidences of toxicities including chronic GVHD and disease progression are currently the
two most important obstacles to this therapy. Better approaches to maintain and improve
benefits of allogeneic transplant, while decreasing toxicity, are urgently needed.
The investigators hypothesize that Bortezomib administration after non myeloablative
allogeneic hematopoietic stem cell transplantation in high-risk myeloma patients might
improved the outcome of these patients by decreasing myeloma relapse and the severity of
chronic GVHD while preserving the graft-versus-myeloma effect. Our goal is to improve the
poor clinical outcome of high-risk myeloma patients.
- Progression-free survival
- Incidence of ≥ grade III non hematologic toxicity (including ≥ grade II peripheral neuropathy) and incidence of ≥ grade IV hematologic toxicity
- Cumulative incidence of grade I-IV and grade II-IV acute GVHD
- Cumulative incidences of chronic GVHD
- Maximum grades of acute and chronic GVHD
- Response rates and quality of responses
- Nonrelapse mortality
- Overall survival
- Incidence of relapse
- Minimal residual disease on bone marrow using multiparametric flow cytometry
- Quality of life after allogeneic transplantation
To date, the only potential curative treatment for multiple myeloma remains allogeneic
hematopoietic stem cell transplantation. Achievement of remission in myeloma patients
allotransplanted with advanced disease, achievement of complete response in relapsed
patients following infusion of donor leucocyte infusions, decreased incidence of relapse
associated with chronic GVHD, better survival in myeloma patients who have relapsed after
allogeneic transplant with rescue medication and production of an allo-immune response after
allogeneic transplant, all support the existence of a graft-versus-myeloma effect. However,
chronic GVHD participating to the morbidity and mortality of allogeneic transplantation, in
addition to the significant relapse rate despite the transplantation are two important
obstacles to this therapeutic modality in myeloma.
Bortezomib (VelcadeTM) is a dipeptidyl boronic acid-based reversible proteasome inhibitor.
Several mechanisms of action have been proposed for its effects against multiple myeloma:
direct induction of myeloma cells apoptosis, inhibition of NF-κB activation, reduction of
myeloma cells adherence to the bone marrow microenvironment (decreasing drug resistance),
inhibition of production, secretion and intracellular signalling of myeloma-mediators. It is
one of the most effective drugs in the treatment of multiple myeloma. As consolidation
treatment after autologous stem cell transplantation, the drug has been associated with an
improvement in response rate and more importantly, in quality and depth of response.
Maintenance treatment with Bortezomib after autologous transplantation has led to survival
improvement, a benefit particularly obvious in myeloma patients with high-risk cytogenetics
such as those carrying del(17p13).
In addition to its anti-myeloma properties, Bortezomib has immunomodulatory effects. Indeed,
proteasome inhibitors affect several aspects of immune and inflammatory responses by
interfering with antigen presenting cell function and effector cell function. Given its
immunomodulatory properties, Bortezomib has recently been shown to be safe and effective in
HLA-mismatched reduced-intensity conditioning transplantation as a GVHD prophylaxis.
This is a prospective phase II, open label, single institution study evaluating a novel
treatment strategy in newly diagnosed multiple myeloma patients with high-risk disease or
patients ≤ 50 years old. After an optimal Bortezomib-based induction treatment (VTD, CyBorD,
RVD or PAD [in patients with plasma cell leukemia]) for a minimum of 4 cycles, followed by
Melphalan ≥ 140 mg/m2 and autologous stem cell transplantation, eligible patients who accept
to participate will be included in the study.
Within 6 months of autologous transplantation, patients will receive a non myeloablative
allogeneic transplantation. Patients with a 6/6 compatible sibling donor will receive a
conditioning regimen with Fludarabine 30 mg/m2 and Cyclophosphamide 300 mg/m2 per day for 5
days from day -8 to day -4 with 3 rest days before donor stem cell infusion on day 0.
Patients without a sibling donor who have an 8/8 allele matched unrelated donor will receive
a conditioning regimen of Fludarabine 30 mg/m2 per day for 3 days from day -4 to -2 and TBI
2 Gy on day -1 with donor stem cell infusion on day 0.
In sibling transplant recipients, GVHD prophylaxis will consist of Tacrolimus 3 mg p.o. BID
starting on day -8, adjusted thrice weekly to obtain blood levels between 8-12 ng/mL.
Tacrolimus tapering will start day +50 to be completed by day +100 in the absence of GVHD.
In matched unrelated donor recipients, Tacrolimus will be initiated as in siblings, but
started on day -4, and taper will be initiated on day +100 to be completed by day +180 in
the absence of GVHD. MMF 15 mg/kg p.o. BID will be given from day +1 to +50 in sibling
recipients. It will be given at same dose but TID from day +1 to +40, then tapered gradually
until day +100 in matched unrelated donor recipients. Patients without progressive disease
after allogeneic transplantation will receive Bortezomib 1.3 mg/m2 s.c. every 14 days ± 3
days starting on day +120, for a total of 26 doses (1 year treatment).
Patients will be followed regularly for disease evaluation, using the IMWG criteria.
Toxicity will be evaluated using the NCI common terminology criteria for adverse events
(CTCAE) version 4.0. Occurrence and severity of acute GVHD will be evaluated using the
modified Glucksberg criteria. Chronic GVHD will be evaluated using the NIH criteria. The
trial will be terminated when all patients have been followed for 5 years after allogeneic
hematopoietic stem cell transplantation.
View this trial on ClinicalTrials.gov